The inhibitory effects of bryostatin 1 administration on the growth of rabbit papillomas
Introduction
The bryostatins are a unique family of 20 naturally occurring macrocyclic lactones which have demonstrated considerable antineoplastic activity. Bryostatin 1 was first isolated from the marine bryozoan Bugula neritina collected off the California coast. B. neritina is a colonial filter-feeder commonly known as a sea-mat or false coral and often grows on docks, pilings, rocks, and ship hulls in temperate ocean areas [1]. Several teams of chemists have succeeded in synthesizing bryostatin 7 and portions of bryostatin 1 [2], but so far the bryozoan is the only source of bryostatin 1 [3].
Both in vitro and in vivo studies have demonstrated the anti-tumor activity of bryostatin 1. For example, bryostatin 1 treatment inhibited the in vitro growth of human lung tumor cells [4], murine reticular cell sarcoma and lymphoma cells [5], and U937 human leukemia cell lines [6]. Bryostatin 1 also induced the differentiation of HL-60 cells [7] and myeloid [8], [9] and lymphocytic [10] human leukemias. The in vivo antineoplastic activity of bryostatin 1 has been shown by its ability to cure mice with ovarian sarcomas [11], P388 lymphocytic leukemia [12], and malignant melanoma [13]. In combination with other therapeutic agents, it has also been shown to cure human Waldenström's macroglobulinemia in SCID mice [14] and to sensitize HeLa cells to cisplatin [15]. Several phase I human clinical trials of bryostatin 1 against a range of cancers have been completed [16], [17], [18], revealing some beneficial effects against malignant melanoma, ovarian carcinoma, non-Hodgkin's lymphoma, and cervical cancer (unpublished).
Although the list of transformed cells against which bryostatin 1 has been tested is extensive, its activity against virus-induced tumors has not been investigated. The discovery that certain urogenital cancers, such as cervical cancer, are highly linked to infection by some types of human papillomaviruses (HPV) has provided an impetus to study these types of transformed cells [19], [20]. HPV DNA is present in 93% of all cervical cancers. Worldwide, cervical cancer ranks second only to breast cancer in both mortality and incidence as the most common human female malignancy with 47 000 new cases diagnosed each year [21]. Of the current therapies available to treat HPV infections, none are capable of eliminating the virus completely, and recurrence rates are high [22]. A more effective treatment for HPV-induced tumors would therefore be of tremendous benefit in reducing the incidence of urogenital cancers.
The cottontail rabbit papillomavirus (CRPV) system is recognized as a good model for human papillomavirus-induced transformation [23]. The present study was undertaken to examine the effects of bryostatin 1 administration on experimentally induced rabbit papillomas. Different routes, doses, and treatment schedules were evaluated in an effort to define optimal therapeutic conditions. We report that bryostatin 1 slows the growth of papillomas when administered either intravenously or intralesionally
Section snippets
Isolation and purification of CRPV-DNA
The plasmid CRPV-pLAII contains the genome of the CRPV Washington B strain. Plasmid was isolated by modification of a method previously described by Cattaneo et al. [24]. Escherichia coli HB101 cells containing CRPV-pLAII (kindly provided by Dr. Janet Brandsma, Yale University) were grown in Terrific broth (1.2% tryptone (Difco, Detroit, MI), 2.4% yeast extract (Difco), 0.4% glycerol) for 18 h at 37°C, shaking at 250 rev./min. The cells were pelleted and resuspended in TEG buffer (25 mM
Intravenous bryostatin 1 administration
Table 1 summarizes the experiments evaluating intravenous bryostatin 1 administration. No dose, route, or schedule of bryostatin 1 administration produced a significant difference in the total number of papillomas formed. Fig. 1 shows that weekly i.v. administration of bryostatin 1 diminished the size of developing papillomas. The average papilloma volume per rabbit in the 2.5 μg/kg group was 92.0% smaller than that of the controls after 70 days (P<0.05) while the volumes in the other two
Discussion
Fig. 3, Fig. 4 show that injections of bryostatin 1 lead to papilloma regression with a concomitant infiltration of heterophils and eosinophils. At least some of bryostatin 1's antineoplastic activity can be attributed to its ability to activate immune cells and stimulate cytokine production. It has been proven to enhance production of hematopoietic growth factors, increase plasma interleukin-6 and TNF-α concentrations, and activate polymorphonuclear leukocytes [16], [27], [28]. Working
Acknowledgements
We would like to thank Steve Moss, Steve Baldwin, David Eldredge, Brett Cherry, and Mata Cain for their assistance in the lab. This study was funded in part by grants from The Brigham Young University Professional Development Committee and the BYU Cancer Research Center.
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